Bleeding Disorders

435 medicine teamwork [ Important | Notes | Extra | Editing file ] ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

lecture objectives:

⇨ Overview of Hemostasis. ⇨ Congenital Disorders. ⇨ Acquired Bleeding Disorders. ⇨ Disorders (Number & Function). ⇨ Approach to the bleeding patients. ⇨ Management of Bleeding patients.

★ I highly advise you to view this 1-page lecture summary before starting the lecture.

Done By​: ​Bedoor Julaidan & Nouf Altwaijri Edited by:​ ​ Rahaf Binabbad Revised By:​ ​ Luluh Alzeghayer & Ahmed Alyahya References: Slides - Master the Boards - Essential Haematology- 433 Medicine team

Overview: Hemostasis

Definition: - The process through which bleeding is controlled at a site of damaged or disrupted endothelium. ​ ​ A dynamic interplay between: •Cellular Components: ( & Endothelium ) ​ ​ •Plasma Proteins Components: 3 protein systems ​ ​ ​ ​ 1.Blood ( Clot Formation ) 2.Fibrinolysis ( Clot Lysing ) 3. ( Regulating ) Whenever the vascular integrity is breached (vessel injury) 3 things happen. Firstly, vasoconstriction, secondly platelet plug formation lastly ​ ​ ​ ​ blood clotting (coagulation cascade) ​ ​ Platelets: - Produced in the Bone Marrow by fragmentation of the cytoplasm of ​ ​ . ​ -Each form 1000 to 5000 platelets. ​ ​ -Time interval from differentiation of the human stem cell to the production of platelets ( ~ 10 days ) -Thrombopoietin → the major regulator of platelets production via ​ ​ c-MPL receptor1 (thrombopoietin is produced by liver (95%) & kidney) ​ ​ -Normal platelets counts ( 150 – 400 x 10⁹ ) -Platelets life span ( 7 – 10 days ) ​ ​ Platelets ultrastructure: Extremely small & discoid (3 x 0.5 µm in diameter) ​ Contains 3 types of storage granules:

α Granules Dense Granules ( δ Granules ) Lysosomes

Clotting Factors ADP & ATP Hydrolytic enzymes VWF (von willebrand factor) Serotonin ​ PDGF2 Histamine IGF13 Ionized Ca Platelets Functions: 1-Adhesion ( Platelets stick to the vessel Wall ) ​ ​ -Adhesion is through attachment of GP Ib-IX-V4 to VWF ​ ​ -VWF is synthesized in endothelial cells & megakaryocytes -VWF is stored in storage granules of endothelial cells & α granules of Platelets -VWF Rises with stress, exercise, adrenaline, infusion of DDAVP (desmopressin) 2-Aggregation ( cross linking of Platelets, platelets stick together ) ​ ​ -Aggregation is through attachment of GP IIb/IIIa receptors (found on ​ ​ platelets’ surface) to VWF and Fibrinogen (mainly fibrinogen) ​ ​ ​ 3-Release Reaction & Amplification ( aggregation formation & stabilization ) ​ ​ -Primary activation by various agonists induces intracellular signaling leading to release of α granules ​ ​ contents (platelets aggregation and stabilization), & ADP (platelets activation) from dense granules ​ ​ ​ ​

1 Thrombopoietin receptor 2 Platelet derived growth factor 3 Insulin like growth factor 4 The GPIb-IX-V complex is a membrane receptor complex present on the platelet surface. ​ ​ ​

-Formation of Thromboxane A2 by various agonists induces intracellular signaling (potentiates platelets ​ aggregation and causes powerful vasoconstriction). ​ *normally the platelets don’t adhere to the endothelium but when there is injury in the endothelium the circulating vWf will attach to subendothelial collagen on one side, and to GP Ib of platelets on the other side. this binding will ​ ​ activate the platelets. When the platelets are activated, they change in shape and receptor becomes activated *normally it is inactive*. Follows that degranulation of platelets’ granules → fibrinogen, vWF, serotonin (which causes vasoconstriction), ADP (important for platelets activation and aggregation) and Ca ( needed in the secondary hemostasis ‘coagulation’). The activated platelets also secretes thromboxane A2 which activates further platelets and causes vasoconstriction. lastly, platelets aggregation mediated by GPIIb/IIIa receptor when it binds to fibrinogen. Many GP IIb/IIIa receptors will attach to single fibrinogen and this what makes platelet plug. Platelets Inhibitors: ● Prostacyclin (PGI₂) -Synthesized by vascular endothelial cells -Potent inhibitor of Platelets aggregation & causes vasodilation by rising cAMP ​ ​ ​ ​ -Prevents Platelets adhesion to normal vascular endothelium ​ ​ ● Nitric Oxide (NO) -Released from endothelial cells, macrophages, & Platelets -Inhibit Platelets activation & promotes vasodilation ​ ​ ​ Coagulation cascade: Intrinsic pathway: We start by factor 12 which activates factor 11. Factor 11 will activate factor 9. Factor 9 in the presence of factor 8 will activate factor 10. Extrinsic pathway: We start by factor 3 (tissue factor) that activates factor 7. Factor 7 activates factor 10 Common pathway: Starting by factor 10 that activates factor 2 (prothrombin) in the presence of factor 5. Prothrombin will activates factor 1 (fibrinogen to fibrin). -Extrinsic pathway is what gets activated in times of injury. but its activation is not sufficient and we need the intrinsic pathway but how the intrinsic pathway gets activated? when factor 7 activates factor 10 and factor 10 activates prothrombin to thrombin, thrombin will activate intrinsic pathway (thrombin activates factor 5,7,8,11,13). Factor 7 also ​ activates factor 9 -The whole idea of coagulation cascade is to generate fibrin, once we ​ ​ generate fibrin we need to cross-link fibrin molecules to stabilize ​ platelet plug in order to form clot, and how this happens? by factor 13, ​ ​ ​ ​ factor 13 enables formation of fibrin mesh ‘clot stabilization’. ​In factor 13 deficiency (rare bleeding disorder) we give them fresh frozen plasma because we don't have it concentrated. -Thrombin is responsible for multiple negative feedback loops that help to control coagulation. one of them is by activating plasminogen to plasmin that breaks fibrin mesh. Thrombin also activates antithrombin that blocks further activation of thrombin and factor 10. At the end of this phase (coagulation ​ cascade) fibrinolysis phase follows. ​ ​

So in summary:

Hemostatic Phases

1.Vascular Phase 2.Platelet Phase 3.Plasma Coagulation 4.Fibrinolysis Phase Phase

-Release of locally Platelets Adhesion & -Propagation of the -Termination of clotting active vasoactive Aggregation (via VWF, clotting process by the by antithrombotic control ​ ​ agents (Endothelin, ADP, TXA2) coagulation cascade of mechanisms & removal Thromboxane A2, -Formation of Platelet coagulation factors. of the clot ​ Fibrinopeptides). Plug. -Formation of Fibrin Clot. ​ ​ -Vasoconstriction at ​ ​ the site of injury reduces blood flow. .

★ The main function of the primary hemostasis is to form Platelet plug ​ ​ ​ ★ The main function of the secondary hemostasis is to form fibrin clot ​ ​ ​ Hemostasis - Helpful Blood Clotting​ 4:48 mins

Approach to Patient with Potential Bleeding

Anticoagulants: The most famous one is , what’s its relation to vitamin K? its one of the major components of the coagulation factors especially if the patient came to you with and prolonged ptt with normal pt + chronic liver disease with high INR vit k is not soluble because of lack of bile so ﻋﻦ k اﻟﺪﻛﺘﻮر ﻣﻤﻜﻦ ﯾﻜﻮن ذﻛﻲ ﺑﺲ ﻣﻮ ﻛﻔﺎﯾﻪ ﻓﺎﯾﺶ ﯾﺴﻮي؟ ﺑﯿﻌﻄﯿﻬﻢ ﻓﯿﺘﺎﻣﯿﻦ there is deficiency of factor five and prolongation of INR, so !ﻃﺮﯾﻖ اﻟﻔﻢ ﺑﯿﻄﻠﻊ ﻣﺎ ﯾﺴﺘﻔﯿﺪ ﻣﻨﻪ اﻟﻤﺮﯾﺾ، ﻻزم ﺗﻌﻄﻮﻧﻪ اﻧﺠﻜﺸﻦ ﻣﻮﻻزم ﺗﻌﺮﻓﻮن اﻟﻬﺎﻓﻼﯾﻒ 1/Detailed patient & family medical history (crucial & vital regardless of the prior lab testing) ​ ​ •Establish likelihood of a bleeding disorder​ • Guide laboratory Testing -Did bleeding occur: •Early in the newborn period (circumcision) ​ ​ •After hemostatic Challenges ( delivery, injury, trauma, surgery, invasive dental ​ ​ procedure, menstruation ) -Frequency & pattern -Duration: •Onset ( congenital vs. acquired ) ​ ​ •Time required for cessation ​ -Sites of bleeding (specific or multiple): Sites of bleeding

Mucocutaneous Bleeding Deep Tissue Bleeding ‘Primary Hemostasis Defects ‘Secondary Hemostasis Defects ( PLT or vW Factor )’ ( Clotting Factors Deficiencies )’

•Easy bruising •Joints •Epistaxis •Muscles •Menorrhagia •Central Nervous System

- Current use of medications or herbal supplements ​ ​ - Use of Bleeding Assessment Tools (differentia bleeding phenotypes, require validation by prospective studies) 2/Laboratory Testing: Screening Tests: 1.CBC (Platelet count) ​ ​ 2.Prothrombin Time (PT) → measures FVII, X, V, II, I - (normal time 10-14 secs) “extrinsic pathway” ​ ​ ​ ​ 3.International Normalized Ratio (INR) → the ratio of a patient's PT to a normal (control) sample, raised to ​ ​ the power of the ISI (international sensitivity index) value for the control sample used. 4.Activated Partial Thromboplastin Time (aPTT or PTT) → measures F XII, XI, IX, VIII, X, ​ ​ V, II, I - (normal Time 30 – 40 secs) “intrinsic pathway” 5.Thrombin (Clotting) Time (TT) → sensitive to deficiency of Fibrinogen or inhibition of thrombin - (normal ​ ​ Time 14 – 16 secs) 6.Bleeding Time → (3-8 secs) (not sensitive – not specific ) ​ ​ -Screening tests (not sensitive to all abnormalities associated with a bleeding disorder) -Although screening tests are used widely to identify hemostatic abnormalities associated with bleeding, they are NOT perfect -The Clinical suspicion for a bleeding disorder is Critical to determine extent of the laboratory ​ ​ investigations Specialized Tests 1.Mixing Study (one to one mixture of patient’s plasma & known normal standard plasma, only if PT or ​ ​ ​ ​ ​ ​ aPTT prolonged) ​ Corrected → clotting factor deficiency (risk of bleed) ​ Not corrected → inhibitors or antibodies directed against the clotting factors (directed against specific ​ ​ ​ factor or global inhibitors “ Inhibitor, risk of “) 2.Platelets Function Assay (PFA - 100): assess platelets function → Specificity 90 % for severe platelets ​ dysfunction of vWD (vWF plasma levels < 25%), Sensitivity 24 – 41 % (low) in mild platelets secretion defect or Storage Pool Disease (not screening tool) Platelet function assay is not done for everyone, only after ​ the results of mixing 3.Platelets Aggregation Tests: (5 external aggregating factors: ADP, Collagen, Ristocetin, Arachidonic Acid, ​ Adrenaline) 4.Von Willebrand Factor (antigen & activity) ​ 5.Factor XIII assay (FXIII Deficiency → normal PT & PTT) ​ ​ ​ 6.Human Plasminogen Activator Inhibitor (PAI-1) ​ 7.Alpha 2 AntiPlasmin Inhibitor (α2 AP) ​

Inherited Bleeding Disorders

Hemophilia: an inherited bleeding disorder caused by deficiency of coagulation factors. ​ ​ ​ ​ (the most common inherited bleeding disorders) ​ ​ اﷲ ﺳﺒﺤﺎﻧﻪ ﺣﻤﻰ اﻟﻨﺴﺎء ﻣﻦ ﻫﺎﻟﻤﺮض، ﻟﻜﻦ اﺣﯿﺎﻧﺎ ﯾﺠﻮﻧﻲ ﺑﺎﻟﻌﯿﺎدة ﻧﺴﺎء ﻓﯿﻬﻢ ﻫﯿﻤﻮﻓﯿﻠﯿﺎ) Hemophilia is an x linked recessive disorder she’s unlucky enough to have both xx affected (her father is affected & her mother is either a ﻛﯿﻒ؟ carrier or also affected). But this is extremely rare! ● Hemophilia A – Inherited deficiency of factor VIII (8); an X-linked recessive disorder. ​ ​ ​ ​ ​ ​ ​Factor 8 deficiency is the most common ● Hemophilia B – Inherited deficiency of factor IX (9); also called Christmas Disease; an X-linked recessive ​ ​ ​ ​ ​ ​ ​ ​ disorder. ● Hemophilia C – Inherited deficiency of factor XI (11); also called Rosenthal Syndrome; variable pattern ​ ​ ​ ​ of inheritance but mainly an autosomal recessive disorder. Rarely, heterozygotes may have bleeding (ie, ​ ​ autosomal dominant transmission, due to heterodimer binding). especially common in Ashkenazi Jews (ie, ​ ​ Jews from Eastern Europe). -Hemophilia most likely is congenital but sometimes can be acquired. ​ ​ Hemophilia

Congenital Acquired

-Genetic mutation in F8 “factor 8” & F9 “factor 9” Development of autoantibodies most commonly ​ ​ ​ located on the long arm of X chromosome. directed against FVIII “or F9, F11”(the factor is ​ ​ ​ ​ -Observed commonly in males due to their produced well but antibodies make it ​ ​ hemizygous state (having only 1 x-chromosome) dysfunctional) – associated with pregnancy, -Rarely in females due to (Heterozygous females malignancy, advanced age. ​ ​ as result from nonrandom X chromosome inactivation ”skewed Lyonization”5, or the presence of other genetic abnormalities (Turner Syndrome or X autosomal translocations). Hemophilia characterized based on the residual or baseline factor activity level (also referred to as "factor ​ ​ level"); expressed as a % of normal or in IU/mL. ​ ​ ​Hemophilia pts present with severe pain in their joint (), we do a baseline factor activity level, <1 is considered severe, >40% is considered normal factor level. Genetic mutation in factor 8 or 9. It also can be acquired, how? Autoantibodies formed against factor 8, common in pregnancy, malignancy & unknown causes. Factor levels typically correlate with the degree of bleeding Symptoms. ​ ​ ​ ​ ​ Baseline factor activity level

Severe Hemophilia Moderate Hemophilia Mild Hemophilia

defined as <1 % factor defined as a factor activity level defined as a factor activity level ​ ​ ​ ​ activity (<0.01 IU/mL). ≥1 % of normal and <5 % of ≥5 % of normal and <40 % of ​ ​ ​ ​ ​ ​ normal ( ≥0.01 - <0.05 IU/mL). normal (≥0.05 - <0.40 IU/mL). Usually asymptomatic, we see them when they have undergone dental extraction or surgical procedures

5 Because females have 2 copies of x-chromosome, the process of x chromosome inactivation ensures that females have one functional copy of x chromosome which is the normal dosage for human. random means that the inactivated x chromosome is ​ randomly selected “some women may have 35% of abnormal x chromosome, while others 65% and so on. ​

Clinically presents as: , hemarthrosis, bruising, bleeding (mucosal, GI, GU) Any type of ​ ​ ​ ​ coagulation factor deficiency​ may lead to deep bleeding. ​ Diagnosis: -Prolonged aPTT -Low Factor Level (F VIII or FIX or FXI ) → *the most accurate test* ​ ​ -Mixing study (corrected) → *the initial test* ​ -Normal VWF & PT They present with Hemarthrosis > body responds with inflammation > chronic (alternating pattern of bleeding and inflammation) > destructive arthropathy > replacement of joint but he has severe ،ﺟﺎﻧﺎ ﻣﺮﯾﺾ ﻣﺎ ﻧﻌﺮف ﺗﺸﺨﯿﺼﻪ ﻟﻠﺤﯿﻦ Dx as a hematologist they called you saying abdominal bleeding, his ptt is 70 (double the normal) [suspect coagulation disorder], what's the 1st step to confirm factor deficiency, mixing study! We get the patient’s abnormal ​ plasma and the normal and mix them together, the abnormal has the prolonged ptt. When we mix them, if ptt is back to normal that means there was factor deficiency, ﻻن اﻟﻔﺎﻛﺘﺮ ﻓﻲ اﻟﺒﻼزﻣﺎ اﻟﻜﻮﯾﺲ ﺻﻠﺢ اﻟﺨﻠﻞ ﻓﻲ اﻟﺒﻼزﻣﺎ اﻟﺜﺎﻧﻲ، ﻃﯿﺐ واذا ﺳﻮﯾﻨﺎﻫﺎ وﻣﺎزال ٧٠ اﯾﺶ اﻟﻤﺸﻜﻠﺔ؟ acquired autoantibodies ﺣﺘﻰ ﻟﻤﺎ ﺗﺤﻂ ﻓﺎﻛﺘﺮ ﺳﻠﯿﻢ ﻗﺎﻋﺪة ﺗﻀﺮﺑﻪ، ﻓﺎﻟﺤﻤﺪﷲ ﻧﻘﺪر ﻧﻌﺮف اﻻﻧﺘﻲ ﺑﻮدﯾﺰ ﻟﻔﺎﻛﺘﺮ ٨،٩ so we give pt appropriate tx Treatment: Replacement of the deficient coagulation Factor (recombinant or plasma derived) + ​ ​ Adjunctive therapy​ (Desmopressin (DDAVP), Antifibrinolytic agents (Tranexamic Acid, Aminocaproic Acid), recombinant FVIIa (with inhibitors). -Treat mild cases with Desmopressin -Severe bleeding with low factor level is treated with replacement of specific factor. : -The most common bleeding disorder. -There is either a reduced level or abnormal function of Von Willebrand ​ ​ ​ ​ factor. RIPA: Ristocetin-induced platelet aggregation ​ Most common inherited bleeding disorder is VWD (von willebrand disease). Dx? Ptt can be normal or prolonged based on subtype.

Von Willebrand disease

Congenital Acquired

-Autosomal dominant (most types) Rare, caused by autoantibodies against vWF & immune ​ ​ ​ ​ -Recessive (rarely, type 2M & 3) complex formation, vWF binding to cancer cells, Congenital Heart Disease, Aortic Stenosis, Angiodysplasia. Rx (of the underlying disorder) Clinically presents as: -Typically there is mucus membrane bleeding (epistaxis, menorrhagia). ​ ​ -Easy bruising. Hemarthrosis and muscle hematomas are rare (compared to hemophilia) ​ ​ ​ ​ except in type 3. ​ Diagnosis: -FVIII assay (low in 2N & 3) VWF is the carrier molecule for factor 8 protecting it from ​ ​ ​ ​ premature destruction, that’s why we see low level in some subtypes -Normal aPTT in (Type 1 & 2), prolonged aPTT in (Type 2N, 2B, & ​ ​ 3) Secondary to low levels of FVIII ​ ​ -VWF:Ag VWF antigen level is usually decreased ​ ​ ​ -VWF:RCo Ristocetin cofactor assay: defective platelets ​ ​ ​ aggregation by patient plasma in the presence of ristocetin -VWF multimers (to differentiate subtypes) ​ -Platelets count is normal except for type 2M (in the book 2B not ​ ​ ​ ​ ​ 2M)

Treatment: Desmopressin (DDAVP; intranasal) “Best initial therapy, releases subendothelial stores of VWF” ​ ​ ​ ​ Replacement of exogenous vWF concentrate “if there is no response to desmopressin” ​ ​ Antifibrinolytic agents (Tranexamic Acid, Aminocaproic Acid), Conjugated Estrogens & oral contraceptive Agents (for menorrhagia)

​ ​Platelets Disorders

A) Quantitative platelets disorders: "Most common cause of bleeding → iatrogenic secondary to medications e.g. ” : The list is long you don’t have to memorize it, just go through it ﻟﻮ ﺳﻠﻤﺘﻮا ﻋﺎﻟﻤﺮﯾﺾ ﻣﻤﻜﻦ ﯾﺠﯿﻪ، ﻻ Thrombocytopenia has maaaaany causes .ﺗﺤﻔﻈﻮﻧﻬﺎ اﺣﻨﺎ ﻧﻔﺴﻨﺎ ﻣﺎﺣﻔﻈﻨﺎﻫﺎ - Imuran for example causes thrombocytopenia (from hx! You have to take a good one to know the cause and possible dx) - Pseudothrombocytopenia and the drug induced one are the most common ones in people in the hospitals. اﺣﯿﺎﻧﺎ ﺑﻌﺾ اﻟﻨﺎس ﻟﻤﺎ ﻧﺴﺤﺐ ﻣﻨﻬﻢ دم ﺗﺘﺠﻤﻊ اﻟﺒﻼﺗﻠﺘﺲ ﺣﻘﺘﻬﻢ ﺳﻮا، ﺗﺘﺨﺾ :In vitro condition ﻛﺪه وﺗﺮح ﻻﻣﻪ ﺑﻌﻀﯿﻬﺎ، ﻓﻠﻤﺎ ﻧﺤﻄﻬﺎ ﻓﻲ اﻟﻤﺸﯿﻦ اﻟﻐﺒﯿﺔ ﺑﺘﻌﺪ اﻟﺨﻤﺴﺔ ﺑﻮاﺣﺪ ﻓﯿﺼﯿﺮ اﻟﻌﺪد ﺑﺪل ٢٠٠ ﻛﻢ؟ ٤٠! وش اﺳﻮي اﻧﺎ؟ اروح اﻗﻮل ﺳﻮوﻫﺎ manual counting .. ﯾﺮوح ﺣﺎﻃﻬﺎ ﻋﻠﻰ ﺳﻼﯾﺪ وﯾﻌﺪﻫﺎ وﺣﺪه وﺣﺪه و ﯾﺮﺟﻊ ﯾﻘﻮﻟﻚ ﺻﺎرت ٢٠٠ ^that’s “pseudothrombocytopenia” Approach to Thrombocytopenia:

-When you do a CBC and it shows thrombocytopenia, you do peripheral blood smear and if there is platelets clumping it means that the machine counted the clumped platelets as one so that’s why it showed thrombocytopenia (we call it pseudothrombocytopenia because the patient is not thrombocytopenic). -If we have true thrombocytopenia we have variety of possibility: 1- Thrombotic thrombocytopenic “hemolytic uremic syndrome” & DIC : we see schistocytes which are fragmented parts of a red blood cells as they pass through fibrin strands and they are generated by these diseases processes “ TTP/HUS/DIC” 2- Blasts, nucleated RBCs typically seen with bone marrow disorders 3- is a very rare autoimmune disorder in which the destroys the body's red blood cells , white blood cells and/or platelets “autoimmune hemolytic anemia (AIHA)” resulting in spherocytes formation “erythrocytes that are sphere-shaped rather than biconcave disk shaped”

4-Elevated levels of or indicative of underlying infection causing thrombocytopenia 5-Isolated thrombocytopenia typically seen in ITP “idiopathic ” We will discuss ITP - TTP - DIC. Immune Thrombocytopenic Purpura (ITP): - The highest incidence has been considered to be in women aged 15-50 years ​ ​ - The lifespan of platelets reduced to only few hours - Increased in platelets turnover and increase in megakaryocytes number - It is usually idiopathic but it might be secondary Very common disorder of platelets especially in younger females if <100000 you have to consider this diagnosis! But you must consider everything else because it's a diagnosis of exclusion, so if everything else is negative this is your diagnosis. ITP

Primary Secondary

Isolated thrombocytopenia “no anemia or Associated with disease or drug exposure: ​ ” due to immune mediated Viral (HIV, HCV, HBV, EBV, CMV, Parvovirus), SLE, ​ ​ platelets destruction (production of APLS “antiphospholipid antibody syndrome” , H. autoantibodies against platelets.) Pylori Infection, Chronic Lymphocytic Leukemia (CLL), Hodgkin Lymphoma, AIHA “autoimmune hemolytic anemia” Clinical features: insidious onset of mucocutaneous bleed, F:M (3:1) ​ ● Immune destr​ uction is peripheral not central. ● Suppressed production in bone marrow ● Could be 2ndary to other causes. ● Thrombocytopenia and leukopenia and you didn't check bone marrow? Fatal mistake! ● If you give them steroids and the number is raised to 150000 now it will confirm your diagnosis because it's an immune disorder. ● Thrombocytopenia with splenomegaly? Hypersplenism (it causes thrombocytopenia more than leukopenia) Diagnosis: Diagnosis of exclusion, no robust clinical or Lab parameters, Typically: ​ - CBC ​ (Isolated​ thrombocytopenia < 100.000) ​ ​ - Peripheral blood smear shows large platelets ​ - Anti-platelets antibodies (not useful) - 10% have associated ITP + AIHA (Evans Syndrome) - Bone marrow shows normal or increased number of megakaryocytes Treatment: - Rarely​ indicated if platelets > 50.000 unless there is bleeding, trauma/surgery, anticoagulation, comorbidities - Steroids, IVIG, , if all fail >TPO agonists ​ ​ ​ ​ ​ (Romiplostim, Eltrombopag) Acute exacerbation: ● First: steroids! Don't give platelet transfusion because it will fire up the you must give ﺣﻄﻮ ﺗﺤﺘﻬﺎ اﻟﻔﯿﻦ ﺧﻂ antibodies more so patients won't benefit unless they have serious bleeding them platelets. ● Second: IV Ig immunoglobulin, in 2 days it will fix it all up! ○ Eg pregnant lady, platelet count 2000 tomorrow she'll give birth so what to do? Give IV Ig and وﺗﻮﻛﻠﻮا ﻋﻠﻰ اﷲ وﻟﺪوﻫﺎ tomorrow it will be 70 000 ○ Steroid dose 1g per kilo, IVIG 1mg per kilo ● Forget about anti Rh!

Thrombotic thrombocytopenic purpura (TTP-HUS) Etiology: 1. TTP​ is a rare disorder of platelet consumption. The cause is unknown. 2. Hyaline microthrombi (mostly platelet thrombi) occlude small vessels—any organ may be involved. They cause mechanical damage to RBCs (schistocytes on peripheral smear). 3. This is a life-threatening emergency that is responsive to therapy (see below). If untreated, death occurs within a few months. Clinical features: 1. Hemolytic anemia (microangiopathic) 2. Thrombocytopenia 3. Acute renal failure (mild) 4. Fever 5. Fluctuating, transient neurologic signs—can range from mental status change to hemiplegia Treatment: 1. Plasmapheresis (large volume). Begin as soon as diagnosis is established (delay in treatment is life-threatening). Response is usually good (monitor platelet count, which should increase). 2. and splenectomy—may be of benefit in some cases 3. Platelet transfusions are contraindicated.

Disseminated Intravascular Coagulation (DIC) Etiology: ​ - Trauma, shock, infection, malignancy (esp APML6), Obstetric complications. Common as well in the ​ critically ill pt Pathogenesis : - Massive activation of coagulation that overwhelms control mechanisms → thrombosis ​ Acute consumption of coagulation factors & Plts → bleeding ​ ○ Ongoing thrombosis and bleeding the coagulation system went crazy! ﺗﺼﯿﺮ ﺿﺎرﺑﺔ ﻓﻲ اﻟﺴﻤﺎ و اﻟﺒﻼﺗﻠﯿﺖ واﻟﻔﺎﯾﺒﺮﯾﻨﻮﺟﻦ ﻧﺎزﻟﻪ و ptt and INR ،ﺗﺎﺧﺬ ﻣﻌﻬﺎ اﻟﻜﻮاﻗﯿﻠﻮﺷﻦ ﻓﺎﻛﺘﻮر ﻓﯿﺼﯿﺮ ﻧﺎزل Platelets ○ اﻟﻔﺎﯾﺒﺮﯾﻨﻮﻟﯿﺘﻚ ﺳﺴﺘﻢ ﺷﻐﺎل Diagnosis: - PT and​ aPTT are elevated ​ - Decreased level of fibrinogen (may be normal because of acute phase) ​ - positive D-Dimer/FDP7 - Decreased level of platelets, ​ - positive Schistocytes - High LDH - Low Haptoglobin Diagnosis of exclusion, treat the underlying cause! You can't do anything else! Treatment: No treatment ​ ​ - Treat underlying process, FFP8, Cryoprecipitate (Goal Fibrinogen > 100 mg/dL), Platelets concentrate

B) Qualitative platelets disorders: Acquired Platelets Functional Disorders: 1. Liver Disease. 2. Cardiopulmonary Bypass. 3. Uremia. 4. Dysproteinemia (Multiple Myeloma or Waldenstrom Macroglobulinemia).

6 Acute Promyelocytic Leukaemia 7 fibrin degradation product 8 Fresh frozen plasma

5. Myeloproliferative Disorders (MPDs). 6. Diabetes Mellitus. 7. Acquired Glanzmann thrombasthenia. ● Platelet normal but not functioning ● Advanced renal failure + urea can cause it ● The list is long اﺣﻔﻈﻮا اﺗﻨﯿﻦ...وﺣﺘﻰ اﻻﺗﻨﯿﻦ ﻛﺘﯿﺮ ﻋﻠﯿﻜﻮ →Inherited Disorders Of Platelets Function: Inherited Giant platelet disorders includes Plt GP abnormalities​ ​ (eg, Bernard-Soulier Syndrome, Deficiency of ​ ​ Platelet Alpha granules (eg, ), Deficiency May-Hegglin Anomaly (which also involves the presence of abnormal inclusions (ie, Döhle-like bodies)), & some kindreds with type 2B vWD (Montreal Platelets Syndrome) 1. Wiskott-Aldrich syndrome 2. Storage Pool Disorders such as Hermansky Pudlak Syndrome (HPS) (Deficiency of Dense Granules) 3. Glanzmann thrombasthenia 4. Platelet release disorders 5. Glycoprotein VI defects 6. 7. Congenital Deficiency of the ADP receptor P2Y12 8. Scott syndrome

INHERITED DISORDERS OF PLATELETS FUNCTION اﻻﺛﻨﯿﻦ اﻟﻠﻲ ﯾﻘﺼﺪﻫﺎ اﻟﺪﻛﺘﻮر

Bernard-Soulier Syndrome Glanzmann thrombasthenia

• Autosomal recessive disease • Autosomal recessive disease • Disorder of platelet adhesion (to • Disorder of platelet aggregation due to deficiency ​ ​ ​ ​ subendothelium) due to deficiency of platelet in platelet glycoprotein GPIIb-IIIa ​ glycoprotein GPIb-IX • Bleeding time is prolonged. ​ • On peripheral blood smear, platelets are • Platelet count is normal. ​ ​ abnormally large. • Platelet count is mildly low. ​ ​

Tranexamic acid for the ﻣﻦ ﺑﻄﻞ ﻫﺎﻻﻣﺮاض؟ ,How to treat? Platelet transfusion because it's inherited ● mucocutaneous bleeding is more effective, the visceral not as much. ______

Drugs used for clotting disorders: (preventing formation of blood clots) ​

Direct Thrombin Indirect Thrombin Vitamin K epoxide Direct Xa Inhibitors Inhibitors Inhibitors reductase Inhibitor

Dabigatran Unfractionated Heparin Warfarin Rivaroxaban a new ​ ​ Argatroban (UFH) medication where we don’t Lepirudin LMWH - Enoxaparin need to monitor PT and PTT and it is taken orally Bivalirudin LMWH - Tinzaparin Apixaban LMWH - Deltaparin Endoxaban Fondaparinux

Antiplatelets

Prostaglandin/COX Inhibitors Glycoprotein IIb/IIIa Inhibitors P2Y₁₂ ADP Inhibitors

Aspirin Abciximab Eptifibatide Cangrelor Tirofiban Prasugrel Ticlopidine Ticagrelor

Thrombolytics (Plasminogen Activators)

Tissue Plasminogen Activators(t-PA) Streptokinase (SK) Urokinase (UK)

Alteplase - - Reteplase Teneteplase

MCQs

1) 13 year old female came in with mucocutaneous 3) 14 years old male patient presented with epistaxis and bleeding and petechiae. Platelets were low at 1500, gingival bleeding, the patient denied any other bleeding, autoimmune and viral screen were negative. Rest of fever, lymphadenopathy. The platelet count was 9000 he CBC is normal. What is the most likely diagnosis? had severe thrombocytopenia, peripheral Smear showed no evidence of ruptured or abnormal blood cells. LDH level was A. immune thrombocytopenic purpura 153 (normal). What is the best management in this case? B. Glanzmann's disease A. Fresh frozen plasma C. Bernard lousier B. Plasmapheresis D. vWF Summary of lab findings: 2) You have been called from obstetrician due to a severe bleeding after delivery. Normal PT, aPTT and platelets count and she has a brother diagnosed with bleeding disorder. What is the deficient factor? A. factor VII B. factor VIII C. factor XIII

Answer key: 1 (A) | 2 (C) | 3 (A) | 4 () | 5 () ​ ​ ​ ​ ​ ​ ​ ​